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Investigation of HDAC Inhibition on Bovine Mammary Cell Inflammation via Phosphate-Dependent Regulation of JNK Signaling
AdvisorFerguson, Bradley S.
Cellular Molecular Biology
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Mastitis, inflammation of mammary gland tissue, occurs in all lactating vertebrates. In dairy cattle, mastitis is the most common and costly disease in which chronic inflammation of mammary epithelial cells disrupts endothelial barrier integrity, compromising the health of extravascular tissues. Despite established prevention methods and antibiotic treatment, approximately 75% of dairy cattle in the U.S. suffer from mastitis each year, highlighting the need for improved therapeutic strategies. Small molecule histone deacetylase (HDAC) inhibitors have been proven efficacious in suppressing inflammation and inflammatory signaling. Data presented in this thesis used bovine MAC-T cells stimulated with tumor necrosis factor ? (TNF?) as a model of mastitis. We report that inhibition of class I HDACs significantly attenuates TNF?-induced mammary cell inflammation, in part, via suppression of c-Jun N terminal kinase (JNK) signaling. Moreover, we demonstrate that treatment with HDAC1/2-specific inhibitors completely ablates JNK signaling. The implication of these findings suggests potential therapeutic applications for small molecule HDAC 1/2-specific inhibitors for the treatment of bovine mastitis; future research is needed to establish therapeutic efficacy in vivo.